WO2019140203A1 - Normalisation de la pression artérielle avec stimulation épidurale de la moelle épinière - Google Patents

Normalisation de la pression artérielle avec stimulation épidurale de la moelle épinière Download PDF

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WO2019140203A1
WO2019140203A1 PCT/US2019/013212 US2019013212W WO2019140203A1 WO 2019140203 A1 WO2019140203 A1 WO 2019140203A1 US 2019013212 W US2019013212 W US 2019013212W WO 2019140203 A1 WO2019140203 A1 WO 2019140203A1
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blood pressure
individual
spinal cord
stimulation
electrical stimulation
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PCT/US2019/013212
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English (en)
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Susan J. HARKEMA
Claudia Angeli
Yangsheng Chen
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University Of Louisville Research Foundation Inc.
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Priority to AU2019207902A priority Critical patent/AU2019207902A1/en
Priority to EP19738794.7A priority patent/EP3737462A4/fr
Priority to US16/960,447 priority patent/US20200346015A1/en
Publication of WO2019140203A1 publication Critical patent/WO2019140203A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0031—Implanted circuitry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/0205—Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/021—Measuring pressure in heart or blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/024—Detecting, measuring or recording pulse rate or heart rate
    • A61B5/02416—Detecting, measuring or recording pulse rate or heart rate using photoplethysmograph signals, e.g. generated by infrared radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
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    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1495—Calibrating or testing of in-vivo probes
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    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/296—Bioelectric electrodes therefor specially adapted for particular uses for electromyography [EMG]
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    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
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    • A61N1/36114—Cardiac control, e.g. by vagal stimulation
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Definitions

  • Methods for normalization of blood pressure for individuals with spinal cord injuries include providing such individuals with spinal cord electrical stimulation optimized for cardiovascular function.
  • An electrode array provides specific stimulation configurations (anode and cathode electrode selection, voltage, frequency and pulse width) identified to maintain systolic blood pressure within targeted normative ranges without skeletal muscle activity.
  • Cardiovascular dysfunction is a leading cause of death in individuals with spinal cord injury and has a significant negative impact throughout their lifetime.
  • Individuals with chronic spinal cord injury above T6 experience persistent hypotension and bradycardia, with orthostatic hypotension and severe increases in blood pressure during autonomic dysreflexia resulting in drastic daily fluctuations in cardiovascular activity.
  • This dysregulation of the autonomic system affects their quality of life by causing discomfort, disrupting their ability to participate in rehabilitation, and interfering with their engagement in daily activities of life.
  • Symptoms of chronic low blood pressure and orthostatic hypotension include fatigue, light-headedness, dizziness, blurred vision, dyspnea, and restlessness associated with cerebral hypo-perfusion.
  • CV-scES targeted scES optimized for solely cardiovascular function
  • CV-scES can increase resting blood pressure and attenuate chronic hypotension in individuals with chronic cervical SCI.
  • Four research participants with chronic cervical SCI received an implant of a 16-electrode array on the dura (L1-S1 cord segments, T11-L1 vertebrae).
  • Individual specific CV-scES configurations were identified to maintain systolic blood pressure within targeted normative ranges without skeletal muscle activity of the lower extremities as assessed by electromyography.
  • FIG. 1 depicts a fluoroscopy imaging chart showing electrode array located relative to thoracic and lumbar vertebrae. Large letters T11 , T12, L1 , L2 identify thoracic and lumbar vertebrae; smaller letters L1-S1 identify the spinal cord levels estimated by mapping with motor evoked potentials.
  • FIG 2A includes a series of graphs depicting time courses of electromyography (EMG) and stimulation amplitude during 2 minutes of no stimulation (left), during 2 minutes of stimulation with configuration #1 at 30 Hz (middle) and stimulation with configuration #2 at 60 Hz (right) in one research participant B21. Electrode selection and stimulation frequency are represented on the top right of each section. In the depicted electrode arrays, grey boxes are cathodes, black boxes are anodes, and white boxes are inactive electrodes.
  • EMG electromyography
  • EMG was recorded from the following muscles of the right lower limb: SOL, soleus; MG, medial gastrocnemius; TA, tibialis anterior; MH, medial hamstrings; VL, vastus lateralis; RF, rectus femoris.
  • FIG. 2B includes a series of graphs depicting amplitude of rectified EMG
  • FIG. 2C includes a series of graphs depicting time courses of EMG, electrocardiography (ECG) and continuous blood pressure (BP) in the 10-second windows entered in FIG. 2A.
  • EMG electrocardiography
  • BP continuous blood pressure
  • FIG. 3 includes a pair of graphs depicting (A) systolic blood pressure and (B) heart rate responses to CV-scES in research participant A68 in the presence and absence of electrical stimulation.
  • Systolic blood pressure gradually increased to target range and was maintained during 60 minutes of activation of stimulation (Stim ON) with minimal adjustment in stimulation amplitude, compared with baseline without stimulation (Stim OFF).
  • Heart rate generally showed an inverse relationship with systolic blood pressure.
  • Solid circles represent sitting systolic blood pressure (mmHg, top panel) and heart rate (beats per minute, bottom panel) averaged over every three minutes of beat-to-beat values (mean ⁇ SE).
  • Grey shading area represents the target range of systolic blood pressure (110-120 mmHg). Stimulation (Stim) amplitude is shown in the middle and was continuous throughout the 60 minutes. Frequency was constant at 50 Hz. The vertical dash line indicates the start of stimulation. Electrode configuration is represented on the top right; grey boxes are cathodes, black boxes are anodes and white boxes are inactive electrodes.
  • FIG. 4A is a graph depicting mean arterial pressure response to CV-scES during participants’ first session.
  • Mean arterial pressure was significantly higher during CV- scES when compared with Pre-CV-scES and Post-CV-scES in all of the four research participants A41 (left panel), A68 (middle-left), B21 (middle-right) and A80 (right).
  • Mean arterial pressure was significantly lower during Post-CV-scES compared to Pre-CV-scES in research participant A68 (middle-left) and higher in research participant A80 (right panel).
  • Data points are one-minute averages of mean arterial pressure.
  • FIG. 4B is a graph depicting heart rate response to CV-scES during participants’ first session. Heart rate was significantly lower during CV-scES compared to Pre-CV-scES in research participant A41 (left panel). Heart rate was significantly higher during Post-CV-scES when compared with Pre-CV-scES and CV-scES in all 4 research participants. Data points are one-minute averages of heart rate.
  • Electrode configurations are represented on the bottom left of the bottom graphs, and apply to both FIG. 4A and 4B. Grey boxes are cathodes, black boxes are anodes and white boxes are inactive electrodes. *: p ⁇ 0.0001 ; #: p ⁇ 0.003.
  • FIG. 5 includes a pair of graphs depicting changes in (A) mean arterial pressure (delta mean arterial pressure) and (B) heart rate (delta heart rate) during the first thirty minutes of active CV-scES from Pre-CV-scES, averaged for four research participants for each of five sessions. Mean arterial pressure increased, and heart rate decreased, from Pre-CV-scES to CV-scES in all 5 sessions. Data points are one-minute averages of mean arterial pressure and heart rate subtracted from mean values of Pre-CV-scES.
  • Horizontal line median; solid circle: mean; range of box: interquartile range (25th and 75th percentiles); whiskers: non-outliers maximum and minimum data points; open circles: outliers above or below 1.5* interquartile range.
  • Delta of mean arterial pressure and heart rate of all sessions were significantly different from zero (P ⁇ 0.05).
  • FIG. 6 includes a series of eight graphs, designated A through H, depicting systolic blood pressure responses to optimal vs. non-optimal stimulation configurations in 4 research participants (A41 : A and E; A68: B and F; B21 : C and G; A80: D and H).
  • Optimal stimulation configuration is important as non-optimal configurations failed to increase or maintain systolic blood pressure in the target range.
  • Optimal stimulation configurations are shown in panels A, B, C, and D while non-optimal stimulation configurations are shown in panels E, F, G, and H.
  • Solid circles represent systolic blood pressure averaged over every one minute of beat-to-beat values (meaniSE, left axis).
  • Stimulation was continuous throughout the 10 minutes, black lines represent stimulation amplitude (right black axis) and grey lines represent stimulation frequency (right grey axis).
  • Participant A80 was stimulated with three programs (D and H).
  • D and H thin black line with squares represents stimulation amplitude of program #1 (P1)
  • thick black line represents stimulation amplitude of program #2 (P2)
  • thin black line with crosses represents stimulation amplitude of program #3 (P3).
  • the locations of the squares and crosses in H indicate amplitude changes. Pulse width was 450 ps in all sessions and experiments for all participants.
  • Grey shading areas represent the target range of systolic blood pressure (110-120 mmHg for research participants A41 , A68 and B2; 105-115 mmHg for research participant A80). Electrode configurations are represented on the top right of each graph; grey boxes are cathodes, black boxes are anodes and white boxes are inactive electrodes.
  • CV-scES configurations anode and cathode electrode selection, voltage, frequency and pulse width
  • systolic blood pressure within the range of 110-120 mmHg for research participants A41 , A68 and B21 and 105-115 mmHg for research participant A80, without skeletal muscle activity of the lower extremities as assessed by electromyography in mapping experiments.
  • Exemplary mapping experiments for participant B21 are depicted in FIG. 2A, 2B, and 2C. Such mapping experiments typically required two to three sessions that were limited to two hours each.
  • Noninvasive continuous blood pressure measured from a finger cuff by plethysmographic technique was calibrated and recorded continuously in cardiovascular sessions.
  • the continuous data were sampled with 1000 Hz sampling rate with an A/D converter device and computer interface (Powerlab 30/35 series and Labchart, AD Instruments, Colorado Springs, CO, USA) and stored for offline analysis and was used to guide selection of initial stimulation parameters.
  • Brachial blood pressure measured by oscillometric technique (Carescape V100, GE Healthcare, Milwaukee, Wl, USA) were obtained every 2-4 minutes during the session to calibrate finger blood pressure measurements during the experiments and post-analyses.
  • beat-to-beat systolic and diastolic blood pressure were calculated as the peaks and nadirs of the finger blood pressure waveform, after finger blood pressure was calibrated to brachial levels and internal calibration artifacts were removed.
  • Mean arterial pressure was calculated as one third of systolic blood pressure plus two third of diastolic blood pressure.
  • Heart rate was calculated from the interval between two beats. Beat-to-beat pressures and heart rate were then averaged for every 1 minute for statistical analysis. All analyses were performed with customized software in MATLAB (Mathworks, Natick, MA, USA).
  • Each delta mean arterial pressure, delta systolic blood pressure and delta heart rate value during CV-scES was calculated as the difference of that value and the average of all pre-CV-scES values. These data were not normally distributed and they were also autoregressive (p-value of serial correlation ⁇ 0.05). The signed rank test (comparing medians) adjusted for serial correlation using the method of effective sample size was used to test whether delta mean arterial pressure, delta systolic blood pressure, delta diastolic blood pressure and delta heart rate are different from 0. Statistical analyses were performed in SAS 9.4 (SAS Institute, Inc, Cary, NC, USA).
  • Each individual completes three days of motor mapping of the electrode encompassing voltage response and frequency response curves of local two anode-cathode combinations rostral caudal and left right to determine the initial CV-scES configurations.
  • EMG activity is recorded to identify those combinations that modulate blood pressure but do not elicit motor activity (FIGs. 2A, 2B, and 2C).
  • EMG is at 2,000Hz using a 24-channel hard wired AD board and custom-written acquisition software (Labview, National Instruments, Austin, TX).
  • EMG EMG (MotionLab Systems, Baton Rouge, LA) from the soleus, medial gastrocnemius, tibialis anterior, medial hamstrings, rectus femoris and vastus lateralis using bipolar surface electrodes with fixed inter electrode distance.
  • two surface electrodes were placed over the paraspinal muscles, symmetrically lateral to the epidural electrode array incision site. These two electrodes were used to record the stimulation artifact from the implanted electrode.
  • EMG data were rectified and high-pass filtered at 40 Hz using Labview software customized by our laboratory.
  • Cardiovascular parameters were normalized consistently in four individuals with chronic cervical spinal cord injury using participant specific CV-scES. Prior to stimulation there is often variability in the systolic blood pressure especially when below 90 mmHg as exemplified in participant A68 (FIG. 3). This typically occurs in response to yawning or involuntary muscle activation. Systolic blood pressure was gradually increased to the 110-120 mmHg or 105-115 mmHg range using the participant specific CV-scES configuration and could be maintained with minimal modulations in the stimulation amplitude. The stimulation amplitude was increased to increase systolic blood pressure and decreased to reduce systolic blood pressure to maintain the systolic blood pressure within the target range for 60 minutes. Generally, heart rate was inversely related to systolic blood pressure with some variability over time.
  • CV-scES cardiovascular targeted spinal cord epidural stimulation.
  • Pre-CV-scES before CV-scES.
  • P-value CV- scES versus Pre-CV-scES.
  • CV-scES cardiovascular targeted spinal cord epidural stimulation.
  • P-value change in systolic or diastolic blood pressure versus 0 mmHg.
  • Each individual participant required a specific and unique CV-scES configuration (anode-cathode electrode selection, pulse width, frequency, amplitude) to consistently maintain normalized cardiovascular parameters. All four individuals had different configurations that maintained their systolic blood pressure stable within normal limits (FIGs. 6A-6D). In comparison, other CV-scES configurations not optimized for each individual were unable to consistently maintain blood pressure within the desired range of normalized parameters even when continually modulating stimulation amplitude (FIGs. 6E-6H).
  • stimulating dorsal lumbosacral spinal cord can effectively and safely activate mechanisms to elevate blood pressures to a normal range from a chronic hypotensive state in humans with severe SCI with individual specific CV-scES for a controllable time period when the stimulation is present (FIG. 6).
  • the lower thoracic levels for scES may also be efficacious in raising blood pressure due to the effects of efferent stimulation on the splanchnic vascular bed via sympathetic vasomotor efferents.
  • splanchnic vasoconstriction also could have contributed to venous return and increased blood pressure in response to CV-scES in the participating individuals with hypotension from secondary to chronic SCI, however it seems given that the site of stimulation is more consistent with the activation of the vasomotor sympathetic efferents from the lumbar cord being the more prominent mechanism responsible for the effect observed in this study given the similar location and type of response.
  • other mechanisms must also be considered, for example, given the dorsal location of the electrode, dorsal fibers that project to intermedial lateral columns may reach and influence other levels of the spinal cord and aspects of the autonomic regulatory system.
  • One embodiment of the present disclosure includes a method for controlling blood pressure comprising providing an electrode array comprising a plurality of electrodes, wherein at least one of the plurality of electrodes is configured to deliver electrical stimulation to an individual; determining, for the individual, a configuration of electrical stimulation delivered by the electrode array effective in modifying a blood pressure of the individual; and delivering electrical stimulation to the individual, via the electrode array, according to the configuration.
  • Another embodiment of the present disclosure includes a method of creating an electrical stimulation configuration for controlling an individual’s blood pressure via electrical stimulation, the method comprising defining, for an individual having an implanted electrode array in operative engagement with the individual’s spinal cord, a normalized blood pressure range and a baseline blood pressure, wherein the baseline blood pressure is outside the normalized blood pressure range; providing electrical stimulation to the individual using different combinations of electrodes in the electrode array; identifying at least one combination of electrodes which, when electrical stimulation is provided via the at least one combination of electrodes, modify the individual’s blood pressure without producing a motor function in the individual; determining, for the identified combinations of electrodes, a frequency and amplitude of electrical stimulation effective in shifting the individual’s blood pressure from the baseline blood pressure to the normalized blood pressure range; and defining the electrical stimulation configuration according to the at least one identified combinations of electrodes, the frequency, and the amplitude.
  • a further embodiment of the present disclosure includes a method for increasing blood pressure in an individual, the method comprising delivering to the individual an effective spinal cord epidural stimulation.
  • Another embodiment of the present disclosure includes a system for normalizing blood pressure in an individual with spinal cord injury, the system comprising an implantable electrode array, a pulse generator, and instructions for using the implantable electrode array and the pulse generator to normalize blood pressure.
  • the configuration of electric stimulation includes a pattern of electrode activation, a frequency, a pulse width, and an amplitude.
  • the frequency, the pulse width, and the amplitude are independently controllable in each of the plurality of electrodes.
  • the electrode array is in operative engagement with a portion of the individual’s spinal cord.
  • the electrode array is implanted in operative engagement with thorasic and lumbar vertebrae in the individual’s spinal cord.
  • delivering includes decreasing an amplitude of the electrical stimulation when the individual’s blood pressure exceeds the normalized blood pressure range.
  • delivering includes increasing an amplitude of the electrical stimulation when the individual’s blood pressure is lower than the normalized blood pressure range.
  • the determining comprises activating combinations of electrodes to determine which modify the blood pressure of the individual without producing a motor function in the individual.
  • the individual is a human.
  • spinal cord epidural stimulation is delivered by an implanted electrode array.
  • spinal cord epidural stimulation is optimized for cardiovascular function.

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Abstract

L'invention concerne des procédés de normalisation de la pression artérielle pour des individus atteints de lésions de la moelle épinière, qui consistent à fournir à de tels individus une stimulation électrique de la moelle épinière optimisée pour la fonction cardiovasculaire. Un réseau d'électrodes fournit des configurations de stimulation spécifiques identifiées pour maintenir une pression artérielle systolique dans des plages normatives ciblées sans activité musculaire squelettique.
PCT/US2019/013212 2018-01-12 2019-01-11 Normalisation de la pression artérielle avec stimulation épidurale de la moelle épinière WO2019140203A1 (fr)

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AU2019207902A AU2019207902A1 (en) 2018-01-12 2019-01-11 Normalization of blood pressure with spinal cord epidural stimulation
EP19738794.7A EP3737462A4 (fr) 2018-01-12 2019-01-11 Normalisation de la pression artérielle avec stimulation épidurale de la moelle épinière
US16/960,447 US20200346015A1 (en) 2018-01-12 2019-01-11 Normalization of blood pressure with spinal cord epidural stimulation

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US10485658B2 (en) 2016-04-22 2019-11-26 Backbeat Medical, Inc. Methods and systems for controlling blood pressure
WO2023235722A1 (fr) * 2022-06-01 2023-12-07 Backbeat Medical, Llc Procédés et systèmes de régulation de pression artérielle

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US20200346015A1 (en) 2020-11-05
EP3737462A4 (fr) 2021-05-19
AU2019207902A1 (en) 2020-08-20

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